A Study to Evaluate the Safety and Efficacy of Polatuzumab Vedotin in Combination With Rituximab, Gemcitabine and Oxaliplatin Compared to Rituximab, Gemcitabine and Oxaliplatin Alone in Participants With Relapsed or Refractory Diffuse Large B-Cell Lymphoma

Diffuse Large B-Cell Lymphoma Clinical Trial

— POLARGO  

Official title:

A Phase III, Open-Label, Multicenter, Randomized, Study Evaluating the Safety and Efficacy of Polatuzumab Vedotin in Combination With Rituximab Plus Gemcitabine Plus Oxaliplatin (R-GEMOX) Versus R-GEMOX Alone in Patients With Relapsed/Refractory Diffuse Large B-Cell Lymphoma

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04182204
• Other study ID #: MO40598
• Secondary ID: 2018-003727-10
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: February 7, 2020
• Est. completion date: March 30, 2025

Study information

• Verified date: April 2024
• Source: Hoffmann-La Roche
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study is a multicenter, open-label study of polatuzumab vedotin administered by intravenous (IV) infusion in combination with rituximab, gemcitabine and oxaliplatin (R-GemOx) in participants with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). The study comprises of two stages: a safety run-in stage and a randomized controlled trial (RCT).

Description:

The safety run-in stage (Stage 1) will assess the safety of polatuzumab vedotin plus rituximab, gemcitabine and oxaliplatin (Pola-R-GemOx) in 10 participants. The randomized controlled trial (RCT) (Stage 2) will compare Pola-R-GemOx versus R-GemOx alone using overall survival (OS). This is an event-driven trial.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 270
• Est. completion date: March 30, 2025
• Est. primary completion date: September 30, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Histologically-confirmed diffuse large B-cell lymphoma, not otherwise specified (NOS) or history of transformation of indolent disease to DLBCL

• Relapsed disease (disease that has recurred following a response that lasted = 6 months from completion of the last line of therapy) or refractory disease (disease that did not respond to or that progressed during therapy or progressed within 6 months (< 6 months) of prior therapy)

• At least one (= 1) line of prior systemic therapy:

• Patients may have undergone autologous hematopoietic stem cell transplantation (HSCT) prior to recruitment; In such cases, salvage chemotherapy (e.g., rituximab, dexamethasone, cytarabine, and cisplatin [R-DHAP] and rituximab, ifosfamide, carboplatin, and etoposide phosphate [R-ICE]) will be counted as one line of therapy and conditioning chemotherapy (e.g., BEAM) followed by consolidative autologous HSCT will be counted as one line of therapy

• Patients may have undergone allogeneic HSCT prior to recruitment, so long as they are off all immunosuppressive therapy and have no active GVHD; In such cases, salvage chemotherapy (e.g., R-DHAP and R-ICE) will be counted as one line of therapy and conditioning chemotherapy (e.g., carmustine, etoposide, cytarabine, and melphalan [BEAM]) followed by allogeneic HSCT will be counted as a separate line of therapy

• Participants may have undergone CAR T-cell therapy prior to recruitment. In such cases, cell collection, conditioning chemotherapy, and infusion will be counted as one line of therapy.

• Local therapies (e.g., radiotherapy) will not be considered as lines of treatment

• For participants with a history of the transformation of indolent disease to DLBCL, it is preferred that participants have received at least one treatment for the transformed lymphoma. However, if there are cases where the participants have received an anthracycline-containing chemotherapy regimen (such as R-CHOP) for the indolent lymphoma only, then these participants can be considered as eligible.

• At least one bi-dimensionally measurable lesion, defined as > 1.5 cm in its longest dimension as measured by CT or MRI

• Eastern Cooperative Oncology Group (ECOG) performance status of 0,1 or 2

• Adequate hematological function

• For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraception, and agreement to refrain from donating eggs

• For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating sperm,

Exclusion Criteria:

• History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies (or recombinant antibody-related fusion proteins) or known sensitivity or allergy to murine products

• Contraindication to rituximab, gemcitabine or oxaliplatin

• Peripheral neuropathy assessed to be > Grade 1 according to NCI CTCAE v5.0

• Prior use of polatuzumab vedotin or a gemcitabine plus platinum-based agent combination, recent participation in a clinical trial, and/or treatment with radiotherapy, chemotherapy, immunotherapy, immunosuppressive therapy within 2 weeks

• Planned autologous or allogenic stem cell transplantation or CAR T-cell therapy at time of recruitment

• Primary or secondary central nervous system (CNS) lymphoma

• Richter's transformation or prior CLL

• Abnormal laboratory values or health conditions, as assessed by the investigator, any known conditions preventing adherence to protocol or active bacterial, viral, fungal, mycobacterial, parasitic, or other infection

• Vaccination with a live vaccine within 4 weeks prior to treatment

• Recent major surgery (within 6 weeks before the start of Cycle 1 Day 1) other than for diagnosis

• Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the patient at high risk from treatment complications

• Pregnant or breastfeeding, or intending to become pregnant during the study or within 12 months after the last dose of study drug

• Women of childbearing potential must have a negative serum pregnancy test result within 7 days prior to initiation of study drug

Related Conditions & MeSH terms

• Diffuse Large B-Cell Lymphoma
• Lymphoma
• Lymphoma, B-Cell
• Lymphoma, Large B-Cell, Diffuse

Intervention

Drug:
• Polatuzumab Vedotin
Polatuzumab vedotin 1.8 mg/kg for a maximum dose of 240 mg/cycle IV on Day 1 of each 21-day cycle for up to 8 cycles.
• Rituximab
Rituximab 375 mg/m2 IV on Day 1 of each 21-day cycle for up to 8 cycles.
• Gemcitabine
Gemcitabine 1000 mg/m2 IV on Day 2 of each 21-day cycle for up to 8 cycles.
• Oxaliplatin
Oxaliplatin 100 mg/m2 IV on Day 2 of each 21-day cycle for up to 8 cycle.

Locations

Country	Name	City	State
Brazil	Liga Norte Riograndense Contra O Câncer	Natal	RN
Brazil	Hospital das Clinicas - UFRGS	Porto Alegre	RS
Brazil	Hospital Sao Rafael - HSR	Salvador	BA
Brazil	Hospital das Clinicas - FMUSP	Sao Paulo	SP
Canada	London Health Sciences Centre	London	Ontario
Canada	McGill University Health Centre - Glen Site	Montreal	Quebec
Canada	Niagara Health Systems - St. Catherines General Site; Niagara Health System-St. Catharines Site	St. Catharines	Ontario
Canada	Centre hospitalier regional de Trois-Rivieres	Trois-Rivieres	Quebec
China	Hu Nan Provincial Cancer Hospital	Changsha
China	West China Hospital - Sichuan University	Chengdu City
China	Cancer Center, Sun Yat-sen University of Medical Sciences; Department of Medical Oncology	Guangzhou City
China	The 1st Affiliated Hospital of Nanchang Unversity	Nanchang
China	Guangxi Cancer Hospital of Guangxi Medical University	Nanning City
China	Institute of Hematology and Hospital of Blood Disease	Tianjin City
China	Union Hospital Tongji Medical College Huazhong University of Science and Technology	Wuhan City
China	First Affiliated Hospital of Medical College of Xi'an Jiaotong University	Xi'an
Finland	Oulu University Hospital; Oncology	Oulu
Finland	Tampere University Hospital; Dept of Oncology	Tampere
France	Hopital Henri Mondor; 51 Av Mal Lattre De Tassigny	Creteil
France	CHU de Nîmes - Hôpital Carémeau	Nimes
France	Hopital De Haut Leveque; Hematologie Clinique	Pessac
France	Centre Henri Becquerel; Service Hématologie	Rouen
France	ICANS	Strasbourg
France	Hopital Bretonneau; Hematologie Therapie Cellulaire	TOURS Cedex
Germany	Gemeinschaftsklinikum Mittelrhein gGmbH; Ev. Stift St. Martin	Koblenz
Germany	Universitaetsklinikum Schleswig Holstein - Campus Luebeck; Haematologie, Onkologie	Luebeck
Germany	Universitätsklinikum Ulm; Medizinische Uni-Klinik III Abt. Innere Medizin III Hämatologie u. Onkolo.	Ulm
Greece	Attiko Hospital; Haematology Clinic	Athens
Greece	Laiko General Hospital; Hematology Clinic	Athens
India	Tata Medical Center	Kolkata	WEST Bengal
India	Tata Memorial Hospital	Mumbai	Maharashtra
India	All India Institute of Medical Sciences ,Institute Rotary Cancer Hospital; Department of Oncology	New Delhi	Delhi
Ireland	St James' Hospital; Cancer Clinical Trials Office	Dublin
Italy	Uni Degli Studi Di Bari, Policlinico; Cattedra Di Ematologia,Dipart. Di Medicina Interna E Publica	Bari	Puglia
Italy	Azienda Ospedaliero-Universitaria Policlinico di Modena Ematologia	Modena	Emilia-Romagna
Italy	Ematologia/immunologia Clinica Azienda Ospedaliera Policlinico di Padova	Padova	Veneto
Italy	USL 4 di Prato - Nuovo Ospeale di Prato	Prato	Toscana
Italy	Az. Osp. Uni Ria Policlinico Tor Vergata; Unita Di Ematologia	Roma	Lazio
Korea, Republic of	Pusan National University Hospital	Busan
Korea, Republic of	Chungnam National University Hospital	Daejeon
Korea, Republic of	Gyeongsang National University Hospital	Gyeongsangnam-do
Korea, Republic of	Seoul National University Bundang Hospital	Seongnam-si
Korea, Republic of	Severance Hospital, Yonsei University Health System	Seoul
Mexico	Health Pharma Professional Research	Cdmx	Mexico CITY (federal District)
Mexico	Hospital de Especialidades Centro Medico Nacional La Raza; Haematology	Mexico City	Mexico CITY (federal District)
Mexico	Instituto Nacional de Cancerologia; Oncology	Mexico City
Spain	Hospital Universitari Germans Trias i Pujol; Servicio de Hematologia	Badalona	Barcelona
Spain	Hospital Universitario de Canarias;servicio de Hematologia	La Laguna	Tenerife
Spain	Hospital Univ. 12 de Octubre; Servicio de Hematologia	Madrid
Spain	Hospital Clinico Universitario de Salamanca;Servicio de Hematologia	Salamanca
Spain	Hospital Universitario Dr. Peset; Servicio de Hematologia	Valencia
Turkey	Sakarya Universitesi Egitim ve Arastirma Hastanesi	Adapazari/Sakarya
Turkey	Abdurrahman Yurtarslan Onkoloji Training and Research Hospital	Ankara
Turkey	Akdeniz Uni School of Medicine; Hematology	Antalya
Turkey	Istanbul Uni Istanbul Medical Faculty	Istanbul
Turkey	Istanbul University Cerrahpasa Medical Faculty; Hematology Department	Istanbul
Turkey	Kocaeli Universitesi Tip Fakultesi	Kocaeli
Turkey	Amerikan HAstanesi Onkoloji Birimi Te?vikiye	Ni?anta??
United Kingdom	Beatson West of Scotland Cancer Centre	Glasgow
United Kingdom	Kings College Hospital	London
United Kingdom	Nottingham City Hospital; Dept of Haematology	Nottingham
United States	MSKCC at Basking Ridge	Basking Ridge	New Jersey
United States	MSKCC @ Commack	Commack	New York
United States	Memorial Sloan Kettering Cancer Center at Westchester	Harrison	New York
United States	Memorial Regional Hospital	Hollywood	Florida
United States	Cancer Specialists; North Florida ;Jacksonville (AC Skinner Pkwy)	Jacksonville	Florida
United States	Memorial Sloan Kettering - Monmouth	Middletown	New Jersey
United States	Memorial Sloan Kettering Cancer Center at Bergen	Montvale	New Jersey
United States	Memorial Sloan-Kettering Cancer Center	New York	New York
United States	Nebraska Cancer Specialists; Oncology Hematology West, PC	Omaha	Nebraska
United States	Memorial Cancer Institute at Memorial West	Pembroke Pines	Florida
United States	Memorial Sloan Kettering Nassau	Uniondale	New York
United States	IHA Hematology Oncology Consultants - Ann Arbor; Michigan Orthopedic Center	Ypsilanti	Michigan

Sponsors (1)

Lead Sponsor	Collaborator
Hoffmann-La Roche

Countries where clinical trial is conducted

United States,  Brazil,  Canada,  China,  Finland,  France,  Germany,  Greece,  India,  Ireland,  Italy,  Korea, Republic of,  Mexico,  Spain,  Turkey,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Stage 1: Observed Plasma Concentrations of Polatuzumab Vedotin Antibody-Conjugated Mono-Methyl Auristatin E (acMMAE) and Unconjugated MMAE (ng/mL)	Re-classified as 'Other Pre-specified' due to sparse PK sampling, to support population PK analysis of the data which is an exploratory analysis.	Pre- and post-dose (infusion duration=90 minutes [min]) on Cycle 1 Day 1 and Cycle 4 Day 1 (Cycle length=21 days)
Other	Stage 2: Observed Plasma Concentrations of Polatuzumab Vedotin Antibody-Conjugated Mono-Methyl Auristatin E (acMMAE) and Unconjugated MMAE (ng/mL)	Re-classified as 'Other Pre-specified' due to sparse PK sampling, to support population PK analysis of the data which is an exploratory analysis.	Pre- and post-dose (infusion duration=90 minutes [min]) on Cycle 1 Day 1 and Cycle 4 Day 1 (Cycle length=21 days)
Primary	Stage 1: Percentage of Participants with Adverse Events (AEs)		From baseline until 90 days after last dose (up to approximately 55 months)
Primary	Stage 2: Overall Survival (OS)	Overall survival was defined as the time from the date of randomization to the date of death from any cause.	From randomization in RCT up to approximately 34 months
Secondary	Stage 1: Percentage of Participants with Peripheral Neuropathy	Peripheral neuropathy will be measured by the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity 12-Item Scale (FACT-GOG/Ntx12). FACT-GOG/Ntx12 is a 12-item self-reported questionnaire designed to measure chemotherapy-induced peripheral neuropathy and contains 12 items, covering sensory neuropathy, motor neuropathy, hearing neuropathy, and dysfunction associated with neuropathy.	From baseline up to approximately 71 months
Secondary	Stage 1: Percentage of Participants with Polatuzumab Vedotin Dose Interruptions and Dose Reductions		From baseline up to approx. 55 months
Secondary	Stage 1: Polatuzumab Vedotin Dose Intensity	Dose intensity is defined as the ratio of actual dose administered versus intended dose.	From baseline up to approx. 55 months
Secondary	Stage 1: Percentage of Participants with Anti-drug Antibodies (ADAs) to Polatuzumab Vedotin at Baseline		Baseline (Day 1 of Stage 1)
Secondary	Stage 1: Percentage of Participants with Anti-drug Antibodies (ADAs) to Polatuzumab Vedotin Post-Baseline		Baseline up until Month 2 of the Post-Treatment Follow-up period (up to approx. 55 months)
Secondary	Stage 1: Percentage of Participants with Complete Response (CR)	CR was defined as complete metabolic response assessed by the investigator through PET-CT Scan according to Lugano 2014 response criteria.	From baseline up to approximately 55 months
Secondary	Stage 1: Percentage of Participants with Objective Response (OR)	OR is defined as complete metabolic response (CR) or partial metabolic response (PR) and will be assessed by the investigator through PET-CT scan according to Lugano 2014 response criteria.	From baseline up to approximately 55 months
Secondary	Stage 1: Best Overall Response (BOR)	BOR is defined as the best response recorded from the start of treatment until end of treatment (based on PET-CT or CT data) according to Lugano 2014 response criteria, determined by the investigator	From baseline up to approximately 71 months
Secondary	Stage 1: Progression Free Survival (PFS)	PFS is defined as the time from enrollment to the first occurrence of disease progression (as determined by the investigator according to Lugano 2014 response criteria) or death.	From baseline up to approximately 71 months
Secondary	Stage 1: Overall Survival (OS)	OS is defined as the time from enrollment to death from any cause.	From baseline up to approximately 71 months
Secondary	Stage 1: Event Free Survival (EFS)	EFS is defined as the time from enrollment to the first occurrence of disease progression or relapse, death due to any cause or initiation of any non-protocol-specified antilymphoma treatment (NALT).	From baseline up to approximately 71 months
Secondary	Stage 2: Percentage of Participants with Objective Response (OR)	OR is defined as CR or PR and will be assessed by an Independent review committee through PET-CT scan according to Lugano 2014 response criteria.; OR will also be assessed by the investigator using Response alone (not including PET data) and will consider complete response instead of complete metabolic response.	From randomization in RCT until up to 34 months
Secondary	Stage 2: Percentage of Participants with Complete Response (CR)	CR will be assessed by an Independent review committee through PET-CT scan according to Lugano 2014 response criteria.; CR will also be assessed by the Investigator using Response (not including PET data) and will consider complete response instead of complete metabolic response.	From randomization in RCT until up to 34 months
Secondary	Stage 2: Best Overall Response (BOR)	BOR is defined as the best response recorded from the start of treatment until end of treatment (based on PET-CT or CT data) according to Lugano 2014 response criteria, determined by the investigator	From randomization in RCT until up to 49 months
Secondary	Stage 2: Progression Free Survival (PFS)	PFS is defined as the time from the time of randomization to the first occurrence of disease progression (as determined by the investigator according to Lugano 2014 response criteria) or death.	From randomization in RCT until up to 49 months
Secondary	Stage 2: Duration of Response (DOR)	DOR will be assessed in patients who had an OR, as determined by the investigator, using Lugano 2014 response criteria. DOR is defined as the time interval from the date of the first occurrence of a CR or PR (whichever status is recorded first) until the first date that progressive disease or death is documented, whichever occurs first.	From randomization in RCT until up to 49 months
Secondary	Stage 2: Event Free Survival (EFS)	EFS is defined as the time from enrollment to the first occurrence of disease progression or relapse, death due to any cause or initiation of NALT.	From randomization in RCT until up to 49 months
Secondary	Stage 2: Change From Baseline in European Organisation for Research and Treatment of Cancer (EORTC) Quality-of-Life Questionnaire Core 30 (QLQ-C30) Score	The EORTC QLQ-C30 includes five functional scales (physical, role, cognitive, emotional, social); a global health status (GHS)/quality of life (QoL) scale; and items measuring fatigue, pain, nausea and vomiting, dyspnea, appetite loss, sleep disturbance, constipation, diarrhea, and financial difficulties. The score range for each scale and single-item measure is 0 to 100, where higher scores indicate a higher response level (i.e., better functioning, better QoL, worse symptoms). Key scales included physical functioning, and fatigue, and GHS.	Baseline (Cycle 1 [each cycle is 21 days]), Cycles 2, 3, 5, and 7; 28 days after last dose; and every 2 months during follow up (up to 49 months)
Secondary	Stage 2: Time to Deterioration in Physical Functioning and Fatigue	Time to deterioration in physical functioning and fatigue is defined as the time from randomization to the first documentation of a 10-point decrease in EORTC QLQ-C30 physical functioning and fatigue scales from baseline. The EORTC QLQ-C30 includes five functional scales (physical, role, cognitive, emotional, social); a global health status (GHS)/quality of life (QoL) scale; and items measuring fatigue, pain, nausea and vomiting, dyspnea, appetite loss, sleep disturbance, constipation, diarrhea, and financial difficulties. The score range for each scale and single-item measure is 0 to 100, where higher scores indicate a higher response level (i.e., better functioning, better QoL, worse symptoms). Key scales included physical functioning, and fatigue, and GHS.	Baseline (Cycle 1 [each cycle is 21 days]), Cycles 2, 3, 5, and 7; 28 days after last dose; and every 2 months during follow up (up to 49 months)
Secondary	Stage 2: Change From Baseline in Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) Total Score	The FACT-Lym is a validated health-related quality of life (HRQoL) instrument used specifically in patients with lymphoma. It is composed of the 27-item FACT-general questionnaire (FACT-G), which measures health-related quality of life in patients undergoing any type of cancer therapy, plus the 15-item Lymphoma-Specific Subscale (FACT-Lym LYMS), which assesses the HRQoL impacts of more lymphoma-specific symptoms. Each item of the FACT-Lym is answered using a 5-point scale ranging from 0 = "not at all" to 4 = "very much". 0 = Not at all, 1 = a little bit, 2 = somewhat, 3 = quite a bit, and 4 = Very much. FACT-LYM total score can be calculated and higher scores are reflective of better HRQoL.	Baseline (Cycle 1 [each cycle is 21 days]), Cycles 2, 3, 5, and 7; 28 days after last dose; and every 2 months during follow up (up to 49 months)
Secondary	Stage 2: Time to Progression in Lymphoma Symptoms According to FACT-Lym Subscale	Time to progression is defined as the time from randomization to the first documentation of a 3-point decrease (clinically meaningful change) from baseline.	Baseline (Cycle 1 [each cycle is 21 days]), Cycles 2, 3, 5, and 7; 28 days after last dose; and every 2 months during follow up (up to 49 months)
Secondary	Stage 2: Change from Baseline in Peripheral Neuropathy According to FACT/GOG-NTX-12 Subscale Score	FACT/GOG-Ntx12 is a 12-item self-reported questionnaire designed to measure chemotherapy-induced peripheral neuropathy and contains 12 items, covering sensory neuropathy, motor neuropathy, hearing neuropathy, and dysfunction associated with neuropathy. It is answered using a 5-point scale ranging from 0 = "not at all" to 4 = "very much". 0 = Not at all, 1 = a little bit, 2 = somewhat, 3 = quite a bit, and 4 = Very much. FACT/GOG-Ntx12 subscale scores can be calculated with higher scores reflective of a better outcome.	Baseline (Cycle 1 [each cycle is 21 days]), Cycles 2, 3, 5, and 7; 28 days after last dose; and every 2 months during follow up (up to 49 months)
Secondary	Stage 2: Percentage of Participants with Adverse Events (AEs)		From randomization in RCT until up to 34 months
Secondary	Stage 2: Percentage of Participants with Polatuzumab Vedotin Dose Interruptions and Dose Reductions		From baseline in RCT up to approx. 34 months
Secondary	Stage 2: Polatuzumab Vedotin Dose Intensity	Dose intensity is defined as the ratio of actual dose administered versus intended dose.	From baseline in RCT up to approx. 34 months
Secondary	Stage 2: Percentage of Participants with Peripheral Neuropathy	Peripheral neuropathy will be measured by the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity 12-Item Scale (FACT-GOG/Ntx12). FACT-GOG/Ntx12 is a 12-item self-reported questionnaire designed to measure chemotherapy-induced peripheral neuropathy and contains 12 items, covering sensory neuropathy, motor neuropathy, hearing neuropathy, and dysfunction associated with neuropathy.	From randomization in RCT until up to 49 months
Secondary	Stage 2: Percentage of Participants with Anti-drug Antibodies (ADAs) to Polatuzumab Vedotin at Baseline		Baseline (Day 1 of Stage 2)
Secondary	Stage 2: Percentage of Participants with Anti-drug Antibodies (ADAs) to Polatuzumab Vedotin Post-Baseline		Baseline (Day 1 of Stage 2) up until Month 2 of the Post-Treatment Follow-up period (up to approx. 34 months)